"Medicine is a social science, and politics is nothing else but medicine on a large scale"—Rudolf Virchow

November 07, 2016

​The ECDC Communicable Disease Threats Report (CDTR) is a weekly bulletin for epidemiologists and health professionals about active public health threats. This issue covers the period 30 October to 5 November 2016 and includes updates on West Nile virus, enteroviruses and influenza.

West Nile virus

This week, one new case of West Nile fever has been reported from Bucharest, Romania.

During the June-to-November transmission season, ECDC monitors the situation in EU Member States and neighbouring countries in order to inform the blood safety authorities of areas affected by West Nile fever and changes in the epidemiology of the disease.

Enteroviruses

In early November, Sweden confirmed eight cases with symptoms similar to acute flaccid myelitis whereof 4 with confirmed enterovirus D68.

Since April 2016, Denmark, the Netherlands, Spain, Sweden and United Kingdom (Wales) have reported various severe Enterovirus infections and some have also increased enterovirus detections (the Netherlands and Germany) compared to previous years. The increased detections of enteroviruses associated with neurological symptoms in EU/EEA countries are notable in terms of the severity of symptoms of the reported cases.

ECDC published a rapid risk assessment on 8 August 2016.

Influenza

Activity remained low in the region, with few samples testing positive for influenza viruses (2% of sentinel samples). Levels are similar to those observed for the same period in recent seasons.

November 02, 2016

The Centers for Disease Control and Prevention (CDC) is investigating a national increase in acute flaccid myelitis (AFM) this year, with a surge in recent months, a pattern that may be linked to a recent cluster of suspected cases in Washington state.

Though this year's cases of AFM—marked by sudden onset of limb weakness associated with spinal cord inflammation—haven't reached levels seen in 2014 when the condition first appeared on the national radar with 120 cases reported, the CDC said it is worried about the recent uptick.

No common cause identified

In an update on its AFM page yesterday, the CDC said as of Sep 30, 89 AFM cases have been confirmed in 33 states, mostly in children. The rise in cases from across the country began in August, and the CDC said it has been actively investigating the illness since then.

For comparison, in 2015 the agency received reports of 21 confirmed AFM cases from 16 states.

Despite extensive testing, the CDC hasn't yet determined what's causing the AFM cases. A long list of viruses can cause AFM symptoms, including poliovirus and adenoviruses. The 2014 outbreak coincided with a national outbreak of severe respiratory illnesses caused by enterovirus D68 (EV-D68).

CDC scientists have tested many specimens from patients, but so far they haven't consistently detected a pathogen in spinal fluid, which it said would likely yield good evidence about the cause, given that the illness affects the spinal cord.

The CDC said it's hard to sort out trends with AFM data, because reporting began only in 2014 and is voluntary for most states. Initial years of reporting might contain data variability that makes it hard to compare cases from year to year. "One possible reason for differences in annual reporting is more awareness among and reporting by healthcare providers and health departments," it said.

Washington's cluster rises to 9

Meanwhile, the Washington State Department of Health (WSDH) said in an Oct 28 media statement that it is leading a joint investigation that includes the CDC into a cluster of eight suspected AFM cases, all of them involving children admitted to Seattle Children's Hospital with acute neurologic illness.

October 22, 2016

Enterovirus D68 is classified in the picornavirus family, and shares features with both polioviruses (which cause paralysis but not respiratory disease) and rhinoviruses (which cause respiratory disease but not paralysis). Like human rhinoviruses, EV-D68 initiates infection in the the respiratory tract, but not the intestinal mucosa like poliovirus. Transmission of EV-D68 is by respiratory aerosols (like rhinoviruses), not faecal-oral contamination as for poliovirus. Unlike poliovirus, EV-D68 has not been found in the stool of infected patients.

Although EV-D68 infection has been associated with paralysis in young children, it is not clear if the virus is responsible for this condition. Therefore it is important to determine if EV-D68 is neurovirulent—if it is able to replicate in and destroy neural cells. Until recently we had no clear path to answering this question.

Our work on Zika virus has lead to the establishment of two different systems in our laboratory for studying viral neurovirulence. I previously described our finding that Zika virus can replicate in human cortical neurons produced from human embryonic stem cells. I’ve also described our use of embryonic mice to determine if Zika virus can infect the brain. Both systems could be used to study EV-D68 neurovirulence.

That’s how a research laboratory should work: progress made on one project (Zika virus) can be used to advance our understanding of a different virus (EV-D68). Even though our laboratory is small, we can work on two very different viruses because the experimental approaches are similar.

September 27, 2016

In June and July 2016, we identified 8 adults and 17 children with respiratory enterovirus D68 infections. Thirteen children required intensive care unit admission because of respiratory insufficiency, and 1 had concomitant acute flaccid myelitis. Phylogenetic analysis showed that all of 20 sequences obtained belong to the recently described clade B3.

​The timing of the current enterovirus outbreaks closely follows the usual increase in summer, but reports suggest that seasonal enterovirus activity in the EU/EEA Member States started earlier than in previous years. Some Member States also report an increased frequency of severe disease associated with enterovirus infection.

While it is difficult to interpret these observations in the absence of robust historical data, Member States should consider raising awareness of the importance of including enterovirus infection in the differential diagnosis of neurological and severe respiratory illness. Reporting of enterovirus clusters and outbreaks through the Early Warning and Response System (EWRS) in EU/EEA countries is encouraged. ​

June 16, 2016

​ECDC has published a rapid risk assessment due to a localised outbreak of neurological symptoms associated with enterovirus A71 (EV-A71) in Catalonia, Spain.

Most EV infections, including EV-A71, result in asymptomatic infection. Most symptomatic EV-A71 infections manifest as a self-limiting hand, foot and mouth disease and only a very small proportion of patients develop severe and life-threatening disease. The current outbreak is notable in terms of its magnitude and the severity of symptoms of the reported cases.

The outbreak with neurological complications caused by enterovirus has been ongoing in Catalonia since mid-April 2016, affecting children up to ten years of age. As of 7 June, 87 cases of enterovirus infection with neurological complications have been reported, most of which have evolved favourably, but 22 of the cases remain in hospital, including seven in intensive care units. According to the information received from regional authorities, there are no deaths related to this outbreak. The cases are widespread in Catalonia.

Other EU Member States have not reported concomitant enterovirus outbreaks and ECDC is not aware of signals of other unusual enterovirus outbreaks in the EU.

There is evidence to suggest that the epidemiological pattern of EV-A71 in Europe is going through a change, both due to virus molecular evolution, as well as an increasing likelihood of importation of new virus strains from outside the EU.

The full characterisation of the isolates from the Spanish outbreak, and comparison of these to virus sequences from other countries and continents, should contribute to a better understanding of the changing pattern of EV-A71 epidemiology in Europe.

May 12, 2016

Worldwide emergence of enterovirus (EV) D68 causing severe respiratory illness particularly in children, between 2008 and 2014, has been described in numerous articles. In 2014, EV-D68 gained particular attention when a large outbreak in children, associated with severe respiratory illness and possible neurological illness, occurred in the United States. This event triggered a number of surveillance activities in various countries, some of them published in Eurosurveillance. In our current issue we present investigations into the occurrence of EV-D68 in two European countries namely France and Germany.

The articles present data from patients hospitalised or visiting hospital emergency departments with respiratory symptoms. Schuffenecker et al. report on samples collected by eleven laboratories of the French EV surveillance network from eight of 22 Regions over six months in 2014. These eleven laboratories represent about one-third of the laboratories participating in the French EV network. Böttcher et al. analysed samples during two entire years, 2013 and 2014, at three large tertiary hospital laboratories in Germany. These laboratories, situated mainly in the western part of the country, contribute ca 25% of the EV-positive samples in the nationwide RespVir surveillance.

Both reports are based on a considerable number of screened respiratory samples: 6,229 samples with 212 EV-D68 detections corresponding to 200 cases in France; 14,838 samples with 39 EV-D68-positive cases in Germany.

In line with the literature, the German analysis suggests seasonality of EV-D68 infections, with most cases occurring between September and November (weeks 36‒48), and even though covering only six months, also the French analysis shows peaks in October (week 43) and November (week 48). Moreover, cases in both countries occurred mainly in children younger than five years, although French authors caution that a bias towards preferential sampling of children cannot be ruled out.

We report a cluster of atypical Guillain–Barré syndrome in 10 adults temporally related to a cluster of four children with acute flaccid paralysis, over a 3-month period in South Wales, United Kingdom.

All adult cases were male, aged between 24 and 77 years. Seven had prominent facial diplegia at onset. Available electrophysiological studies showed axonal involvement in five adults. Seven reported various forms of respiratory disease before onset of neurological symptoms. The ages of children ranged from one to 13 years, three of the four were two years old or younger.

Enterovirus testing is available for three children; two had evidence of enterovirus D68 infection in stool or respiratory samples.

We describe the clinical features, epidemiology and state of current investigations for these unusual clusters of illness.

December 22, 2015

Importance There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology.

Design, Setting, and Participants Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing.

Main Outcomes and Measures Case incidence and infectious agent association.

During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid.

The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100 000 person-years) compared with other monitoring periods (0.028 cases per 100 000 person-years; P <.001).

Conclusions and Relevance In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

I posted a few news stories about these cases, including this item on March 20, 2014.

Clusters of acute flaccid paralysis or cranial nerve dysfunction in children are uncommon. We aimed to assess a cluster of children with acute flaccid paralysis and cranial nerve dysfunction geographically and temporally associated with an outbreak of enterovirus-D68 respiratory disease.

Methods

We defined a case of neurological disease as any child admitted to Children's Hospital Colorado (Aurora, CO, USA) with acute flaccid paralysis with spinal-cord lesions involving mainly grey matter on imaging, or acute cranial nerve dysfunction with brainstem lesions on imaging, who had onset of neurological symptoms between Aug 1, 2014, and Oct 31, 2014. We used Poisson regression to assess whether the numbers of cases during the outbreak period were significantly greater than baseline case numbers from a historical control period (July 31, 2010, to July 31, 2014).

Findings

12 children met the case definition (median age 11·5 years [IQR 6·75–15]). All had a prodromal febrile illness preceding neurological symptoms by a median of 7 days (IQR 5·75–8). Neurological deficits included flaccid limb weakness (n=10; asymmetric n=7), bulbar weakness (n=6), and cranial nerve VI (n=3) and VII (n=2) dysfunction. Ten (83%) children had confluent, longitudinally extensive spinal-cord lesions of the central grey matter, with predominant anterior horn-cell involvement, and nine (75%) children had brainstem lesions. Ten (91%) of 11 children had cerebrospinal fluid pleocytosis. Nasopharyngeal specimens from eight (73%) of 11 children were positive for rhinovirus or enterovirus. Viruses from five (45%) of 11 children were typed as enterovirus D68. Enterovirus PCR of cerebrospinal fluid, blood, and rectal swabs, and tests for other causes, were negative. Improvement of cranial nerve dysfunction has been noted in three (30%) of ten children. All ten children with limb weakness have residual deficits.

Interpretation

We report the first geographically and temporally defined cluster of acute flaccid paralysis and cranial nerve dysfunction in children associated with an outbreak of enterovirus-D68 respiratory illness. Our findings suggest the possibility of an association between enterovirus D68 and neurological disease in children. If enterovirus-D68 infections continue to happen in an endemic or epidemic pattern, development of effective antiviral or immunomodulatory therapies and vaccines should become scientific priorities.